Cholinergic neurons which release acetylcholine as a transmitter are widely projected in the forebrain from the nucleus basalis of Meynert and the septal nucleus of the basal forebrain to the hippocampus, amygdala, and cerebral cortex, and are involved in the modulation of memory, learning, cognition, and attention (Non-Patent Literature 1). Moreover, cholinergic neurons in the pedunculopontine tegmental nucleus and laterodorsal tegmental nucleus of the brain stem are projected in the striatum, accumbens nucleus, substantia nigra, and thalamus, and are considered to be involved in the control of motivation and vigilance (Non-Patent Literatures 2 to 4).
In particular, the role of cholinergic neurons in the basal forebrain has been more clarified by analysis using many animal models such as lesion model. Especially, the correlation between functional disorder of cholinergic neurons and decreased memory and learning has been shown in the animal models (Non-Patent Literatures 5 to 7), and it has been shown that cognitive performance is improved by increasing the amount of acetylcholine using a cholinesterase inhibitor, and enhancing the function of cholinergic neurons (Non-Patent Literatures 8 to 12).
It has been reported that Nerve Growth Factor (NGF) shows the neuroprotective effect on cholinergic neurons in the animal model indicating loss of cholinergic neurons. (Non-Patent Literature 13 to 15).
Particularly for Alzheimer's disease (AD), loss of cholinergic neurons is found from early stage of AD and is one of the pathological features of AD. Accumulation of senile plaques by deposits of amyloid beta and neurofibrillary tangles by tau protein aggregation are also pathological features of AD, and particularly neurofibrillary tangles are known to increase with the progress of the disease status and bring neuronal death. Neurofibrillary tangles are found in nucleus basalis of Meynert and entorhinal cortex from the early stage of AD. Among them, it is reported that loss of cholinergic neurons in nucleus basalis of Meynert by tau protein aggregation is found at earlier stage and that there is a correlation between the loss and a decrease in cognitive function score (Non-Patent Literatures 16 and 17). Similarly to AD, hyperphosphorylation and abnormal accumulation of tau protein is found in genetically modified mice having a P301S mutation which has been found in familial frontotemporal dementia (human tau P301S transgenic mice). Consequently, neurofibrillary tangles, a pathological feature of AD, are formed (Non-Patent Literature 18) and bring cognitive dysfunction by synaptic impairment, neurodegeneration and loss of neurons. Based on these findings, human tau P301S transgenic mice are widely used as AD-like animal models (Non-Patent Literatures 19-22), and improvement of cognitive decline and suppression of disease status progress in Alzheimer's disease can be expected by suppressing AD-like pathological changes in human tau P301S transgenic mice.
Furthermore, multiple analyses using genetically modified mice and animal models of disorders suggest that axonal transport deficit is one of the causes of loss of cholinergic neurons (Non-Patent Literatures 23-25). Among them, the axon of cholinergic neurons which projects from septal area to hippocampus is impaired in a fimbria-fornix lesioned model and impairment of retrograde transport of molecules involved with survival and function brings loss of neurons (Non-Patent Literatures 26-28). The impairment of retrograde transport is found also in genetically modified mice (Non-Patent Literatures 23 and 24) and loss of cholinergic neurons by fimbria-fomrnix lesion reflects one aspect of the disease status. Accordingly, improvement of cognitive decline and suppression of disease status progress in Alzheimer's disease can be expected by suppression or improvement of loss of cholinergic neurons in this model of the disorder.
Dementia with Lewy bodies (DLB) and Parkinson disease (PD) are progressive neurodegenerative disorders in which abnormal inclusion bodies (Lewy bodies) mainly composed of alpha synuclein appear in neurons and bring degeneration and loss of neurons. Cognitive dysfunction develops if Lewy bodies are mainly distributed in cerebral cortex and Parkinsonism develops if Lewy bodies are mainly distributed in brain stem. In addition to that, psychiatric symptoms such as visual hallucination, hallucination and delusion, sleep disorder and autonomic symptoms also develop. The diagnosis is dementia with Lewy bodies if dementia appears before or within one year from the onset of Parkinsonism and the diagnosis is Parkinson disease with dementia (PDD) if Parkinsonism has appeared before one year or more from the onset of dementia. Dementia with Lewy bodies, Parkinson disease with dementia and Parkinson disease are pathologically same diseases and comprehensively referred to as Lewy body disease (LBD) though these are different in cognitive dysfunction and appearance order and degree of Parkinsonism. In dementia with Lewy bodies and Parkinson disease with dementia, similarly to Alzheiner's disease, neurons of nucleus basalis of Meynert, a nuclei of origin of cholinergic nerve, are degenerated and lost and it is reported that severe cholinergic neuron disorder appears in hippocampus and cortex (Non-Patent Literatures 29-31). Furthermore, there is a correlation between progress of cholinergic neuron disorder and cognitive dysfunction (Non-Patent Literature 29), and cholinesterase inhibitors have been demonstrated to improve cognitive function. Based on these findings, cognitive function improves by the improvement of function of cholinergic neurons, and similarly to Alzheimer's disease, improvement of cognitive decline and suppression of disease status progress in dementia with Lewy bodies and Parkinson disease with dementia can be expected by suppression or improvement of loss of cholinergic neurons in several models of the disorder.
Therefore, based on these findings, an improvement in reduced cognitive performance caused by the dysfunction of cholinergic neurons can be expected by achieving functional activation and/or neuroprotective effect on cholinergic neurons in clinical practice.
In addition to the above diseases, examples of diseases for which association between decrease in cognitive function and the dysfunction of cholinergic neurons has been reported include Huntington's chorea, Down's syndrome, amyotrophic lateral sclerosis (ALS), major depression, schizophrenia, and the like.